Catheter-based adenovirus-mediated local intravascular gene delivery of a soluble TGF-β type II receptor using an infiltrator in porcine coronary arteries: Efficacy and complications

Ick Mo Chung, Hikaru Ueno, Youngmi Kim Pak, Joon Woo Kim, Donghoon Choi, Gil Ja Shin, Woo Ick Yang, Yangsoo Jang

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Enhanced extracellular matrix (ECM) accumulation is an important finding in human restenotic arterial neointima after angioplasty. Transforming growth factor 1β(TGF-1β) is known to regulate the synthesis and turnover of a variety of ECM components, and may play an important role in restenosis. Recombinant adenoviral vector expressing an ectodomain of the TGF-β type II receptor fused to the human immunoglobulin Fc portion (AdTβ-ExR) inhibits the action of TGF-β probably either by adsorbing TGF-β or by acting as a dominant negative receptor. We carried out a catheter-based local adenovirus mediated gene delivery using an Infiltrator in porcine coronary arteries to know the pattern of gene expression, efficacy and procedural complications. Twenty four coronary arteries in 13 pigs were used for intravascular gene delivery by intramural injection with either AdTβ-ExR or adenovirus expressing β-galactosidase (AdCA-LacZ). Direct immunofluorescent staining and reverse transcription polymerase chain reaction (RT-PCR) were used for detection of type II TGF-β receptor and its mRNA respectively. X-Gal histochemistry was performed to identify β-galactosidase. Both soluble TGF-β receptor and β-galactosidase were expressed locally in the media and adventita at injected arterial segments without any significant dissemination to remote area. Intravascular gene transfection performed with various titer of each adenoviral vector showed that AdTβ-ExR of 5×1O8 pfu and AdCALacZ of 2.5 × 108 pfu were the minimum titer for the expression of each transgene. Infiltration of CD3 positive T cells was detected by immunohistochemical staining in the area of each transgene expression, and tends to decrease over time after gene delivery. Pathological study of 24 treated arteries showed complications such as disruption of external elastic lamina with hemorrhage (n = 4), minimal disruption of internal elastic lamina and endothelial layer, and medial thickening. In conclusion, catheter-based local intravascular gene delivery of adenoviral vector is feasible and effective in a selected artery, but must be undertaken with caution due to possible lethal complications. Local delivery of soluble TGF-β type II receptor in this way may provide an effective intravascular gene therapy to inhibit TGF-β signal pathway without any significant systemic side effect.

Original languageEnglish
Pages (from-to)299-307
Number of pages9
JournalExperimental and Molecular Medicine
Volume34
Issue number4
Publication statusPublished - 2002 Sep 30

Fingerprint

Catheters
Adenoviridae
Galactosidases
Coronary Vessels
Swine
Genes
Transgenes
Extracellular Matrix
Arteries
Staining and Labeling
Immunoglobulin Fc Fragments
Neointima
Gene therapy
T-cells
Polymerase chain reaction
Transforming Growth Factors
Transcription
Angioplasty
Infiltration
Gene expression

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Genetics

Cite this

@article{69daa7534690480aa134bfcc012dd93d,
title = "Catheter-based adenovirus-mediated local intravascular gene delivery of a soluble TGF-β type II receptor using an infiltrator in porcine coronary arteries: Efficacy and complications",
abstract = "Enhanced extracellular matrix (ECM) accumulation is an important finding in human restenotic arterial neointima after angioplasty. Transforming growth factor 1β(TGF-1β) is known to regulate the synthesis and turnover of a variety of ECM components, and may play an important role in restenosis. Recombinant adenoviral vector expressing an ectodomain of the TGF-β type II receptor fused to the human immunoglobulin Fc portion (AdTβ-ExR) inhibits the action of TGF-β probably either by adsorbing TGF-β or by acting as a dominant negative receptor. We carried out a catheter-based local adenovirus mediated gene delivery using an Infiltrator in porcine coronary arteries to know the pattern of gene expression, efficacy and procedural complications. Twenty four coronary arteries in 13 pigs were used for intravascular gene delivery by intramural injection with either AdTβ-ExR or adenovirus expressing β-galactosidase (AdCA-LacZ). Direct immunofluorescent staining and reverse transcription polymerase chain reaction (RT-PCR) were used for detection of type II TGF-β receptor and its mRNA respectively. X-Gal histochemistry was performed to identify β-galactosidase. Both soluble TGF-β receptor and β-galactosidase were expressed locally in the media and adventita at injected arterial segments without any significant dissemination to remote area. Intravascular gene transfection performed with various titer of each adenoviral vector showed that AdTβ-ExR of 5×1O8 pfu and AdCALacZ of 2.5 × 108 pfu were the minimum titer for the expression of each transgene. Infiltration of CD3 positive T cells was detected by immunohistochemical staining in the area of each transgene expression, and tends to decrease over time after gene delivery. Pathological study of 24 treated arteries showed complications such as disruption of external elastic lamina with hemorrhage (n = 4), minimal disruption of internal elastic lamina and endothelial layer, and medial thickening. In conclusion, catheter-based local intravascular gene delivery of adenoviral vector is feasible and effective in a selected artery, but must be undertaken with caution due to possible lethal complications. Local delivery of soluble TGF-β type II receptor in this way may provide an effective intravascular gene therapy to inhibit TGF-β signal pathway without any significant systemic side effect.",
author = "Chung, {Ick Mo} and Hikaru Ueno and Pak, {Youngmi Kim} and Kim, {Joon Woo} and Donghoon Choi and Shin, {Gil Ja} and Yang, {Woo Ick} and Yangsoo Jang",
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Catheter-based adenovirus-mediated local intravascular gene delivery of a soluble TGF-β type II receptor using an infiltrator in porcine coronary arteries : Efficacy and complications. / Chung, Ick Mo; Ueno, Hikaru; Pak, Youngmi Kim; Kim, Joon Woo; Choi, Donghoon; Shin, Gil Ja; Yang, Woo Ick; Jang, Yangsoo.

In: Experimental and Molecular Medicine, Vol. 34, No. 4, 30.09.2002, p. 299-307.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Catheter-based adenovirus-mediated local intravascular gene delivery of a soluble TGF-β type II receptor using an infiltrator in porcine coronary arteries

T2 - Efficacy and complications

AU - Chung, Ick Mo

AU - Ueno, Hikaru

AU - Pak, Youngmi Kim

AU - Kim, Joon Woo

AU - Choi, Donghoon

AU - Shin, Gil Ja

AU - Yang, Woo Ick

AU - Jang, Yangsoo

PY - 2002/9/30

Y1 - 2002/9/30

N2 - Enhanced extracellular matrix (ECM) accumulation is an important finding in human restenotic arterial neointima after angioplasty. Transforming growth factor 1β(TGF-1β) is known to regulate the synthesis and turnover of a variety of ECM components, and may play an important role in restenosis. Recombinant adenoviral vector expressing an ectodomain of the TGF-β type II receptor fused to the human immunoglobulin Fc portion (AdTβ-ExR) inhibits the action of TGF-β probably either by adsorbing TGF-β or by acting as a dominant negative receptor. We carried out a catheter-based local adenovirus mediated gene delivery using an Infiltrator in porcine coronary arteries to know the pattern of gene expression, efficacy and procedural complications. Twenty four coronary arteries in 13 pigs were used for intravascular gene delivery by intramural injection with either AdTβ-ExR or adenovirus expressing β-galactosidase (AdCA-LacZ). Direct immunofluorescent staining and reverse transcription polymerase chain reaction (RT-PCR) were used for detection of type II TGF-β receptor and its mRNA respectively. X-Gal histochemistry was performed to identify β-galactosidase. Both soluble TGF-β receptor and β-galactosidase were expressed locally in the media and adventita at injected arterial segments without any significant dissemination to remote area. Intravascular gene transfection performed with various titer of each adenoviral vector showed that AdTβ-ExR of 5×1O8 pfu and AdCALacZ of 2.5 × 108 pfu were the minimum titer for the expression of each transgene. Infiltration of CD3 positive T cells was detected by immunohistochemical staining in the area of each transgene expression, and tends to decrease over time after gene delivery. Pathological study of 24 treated arteries showed complications such as disruption of external elastic lamina with hemorrhage (n = 4), minimal disruption of internal elastic lamina and endothelial layer, and medial thickening. In conclusion, catheter-based local intravascular gene delivery of adenoviral vector is feasible and effective in a selected artery, but must be undertaken with caution due to possible lethal complications. Local delivery of soluble TGF-β type II receptor in this way may provide an effective intravascular gene therapy to inhibit TGF-β signal pathway without any significant systemic side effect.

AB - Enhanced extracellular matrix (ECM) accumulation is an important finding in human restenotic arterial neointima after angioplasty. Transforming growth factor 1β(TGF-1β) is known to regulate the synthesis and turnover of a variety of ECM components, and may play an important role in restenosis. Recombinant adenoviral vector expressing an ectodomain of the TGF-β type II receptor fused to the human immunoglobulin Fc portion (AdTβ-ExR) inhibits the action of TGF-β probably either by adsorbing TGF-β or by acting as a dominant negative receptor. We carried out a catheter-based local adenovirus mediated gene delivery using an Infiltrator in porcine coronary arteries to know the pattern of gene expression, efficacy and procedural complications. Twenty four coronary arteries in 13 pigs were used for intravascular gene delivery by intramural injection with either AdTβ-ExR or adenovirus expressing β-galactosidase (AdCA-LacZ). Direct immunofluorescent staining and reverse transcription polymerase chain reaction (RT-PCR) were used for detection of type II TGF-β receptor and its mRNA respectively. X-Gal histochemistry was performed to identify β-galactosidase. Both soluble TGF-β receptor and β-galactosidase were expressed locally in the media and adventita at injected arterial segments without any significant dissemination to remote area. Intravascular gene transfection performed with various titer of each adenoviral vector showed that AdTβ-ExR of 5×1O8 pfu and AdCALacZ of 2.5 × 108 pfu were the minimum titer for the expression of each transgene. Infiltration of CD3 positive T cells was detected by immunohistochemical staining in the area of each transgene expression, and tends to decrease over time after gene delivery. Pathological study of 24 treated arteries showed complications such as disruption of external elastic lamina with hemorrhage (n = 4), minimal disruption of internal elastic lamina and endothelial layer, and medial thickening. In conclusion, catheter-based local intravascular gene delivery of adenoviral vector is feasible and effective in a selected artery, but must be undertaken with caution due to possible lethal complications. Local delivery of soluble TGF-β type II receptor in this way may provide an effective intravascular gene therapy to inhibit TGF-β signal pathway without any significant systemic side effect.

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